Synthesis of ibuprofen hybrid conjugates as anti-inflammatory and analgesic agents
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-11850220-B2
Publication Date
2023-12-26
Expiration Date
Abstract
Disclosed herein as ibuprofen hybrid conjugates and methods of their use to reduce inflammation, pain, and fever. The ibuprofen conjugates have potent anti-inflammatory and analgesic properties with low potential for ulcerogenic activity. An exemplary compound is an ibuprofen-amino acid-4-aminophenol hybrid. Also disclosed are methods of treating or reducing inflammation, pain, and fever in a subject.
Core Innovation
The patent relates to ibuprofen hybrid conjugates comprising general structural formulas in which ibuprofen is conjugated to moieties derived from 4-aminophenol or acetaminophen. The disclosed conjugates include variable linker groups and substituent definitions expressed through R1, R2, and R3/R4, and can be present as enantiomers, tautomers, stereoisomers, solvates, zwitterions, polymorphs, prodrugs, or pharmaceutically acceptable salts.
The patent further describes ibuprofen hybrid conjugates defined by a general formula (i) and by specified compound structures, including ibuprofen-amino acid conjugates and ibuprofen-amino acid-4-aminophenol conjugates such as Ibu-L-Met-4AP and Ibu-L-Gln-4AP and related compounds. The disclosed subject matter is positioned within a structure-activity relationship framework and is directed to maintaining therapeutic benefit for inflammation and pain while reducing ulcerogenic risk associated with ibuprofen.
The invention also includes pharmaceutical compositions comprising an effective amount of at least one ibuprofen hybrid conjugate and pharmaceutically acceptable excipients. The disclosed embodiments include administration routes such as oral and parenteral, and therapeutic indications directed to treating inflammation, inducing analgesia, reducing fever, and addressing inflammation symptoms, pain of varied etiologies, and fever reduction.
Claims Coverage
The record provides two independent claim families: a broad genus defined by a general ibuprofen hybrid conjugate chemical formula with variable substituents and stereochemical or physicochemical variants, and ibuprofen hybrid conjugates defined by the structures of listed compounds, optionally as pharmaceutically acceptable salts.
General-formula ibuprofen hybrid conjugate
An ibuprofen hybrid conjugate defined by a general formula in which R1, R2, and R3/R4 are independently selected from the enumerated group types, and wherein the conjugate may further be an enantiomer, tautomer, stereoisomer, solvate, zwitterion, polymorph, prodrug, or a pharmaceutically acceptable salt thereof.
Listed-structure ibuprofen hybrid conjugate
An ibuprofen hybrid conjugate comprising the structure of any of the listed compounds, or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage centers on a structurally defined ibuprofen hybrid conjugate genus specified by a general formula with broadly enumerated substituent options and derivative or stereochemical forms, and on ibuprofen hybrid conjugates defined by inclusion of specified structures, including pharmaceutically acceptable salts.
Stated Advantages
Improved anti-inflammatory potency is reported for select ibuprofen-amino acid-4-aminophenol conjugates in the carrageenan-induced paw edema test versus indomethacin and/or ibuprofen.
Lower ulcerogenic liability versus indomethacin and ibuprofen.
Improved toxicological safety.
Peripheral and central analgesic performance.
Anti-inflammatory activity supported by COX-1/2 inhibitory assay outcomes including IC50 values and selectivity index (COX-2/COX-1).
Modeling support for anti-inflammatory activity, supported by 2D-QSAR and 3D-pharmacophore modeling correlations.
Potent anti-inflammatory and analgesic effects with reduced ulcerogenic risk.
Support for fever reduction.
Documented Applications
Treating inflammation by administering a pharmaceutical composition containing at least one ibuprofen hybrid conjugate, in an effective amount, to reduce inflammation in a subject.
Reducing pain by administering a pharmaceutical composition containing at least one ibuprofen hybrid conjugate, in an effective amount, to reduce pain in a subject.
Treating inflammation by administering a pharmaceutical composition comprising an effective amount of at least one ibuprofen hybrid conjugate, or pharmaceutically acceptable salt.
Reducing pain by administering the pharmaceutical composition of an effective amount to a subject.
Inflammation symptoms.
Pain of varied etiologies.
Fever reduction.
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